Langston is founder, CEO and scientific director of The Parkinson's Institute, a non-profit organization that operates comprehensive research and treatment programs dedicated to finding the cause of Parkinson's, developing a cure and improving patient care. Langston dedicated his career to studying Parkinson's after discovering, in 1982, a link between a toxin found in a form of synthetic heroin and the near-immediate onset of Parkinson's symptoms.

“Is it a curable disease? No. Do we have a way to slow it down, that's proven? No. But those are all in the pipeline, and I think could happen in our lifetime. So I give patients a very positive message.”

Let me ask you first, Bill, about the challenge in solving any of these neurological conditions. Where are we with that?

I think one of the great challenges working on Parkinson's disease or any similar neurodegenerative disease, including Alzheimer's, is that we have never really solved any of them yet. We don't know the cause. We don't completely understand the reasons cells die in the brain in these diseases, and we have never found a way to stop progression or cure the disease. These are all great unknowns, so the challenges are enormous.

And why would finding a way over that obstacle -- understanding something about what's amiss, let's say, in Parkinson's -- be significant, not only for Parkinson's but potentially for other neurological conditions as well?

Well, I think there's a general sense in the scientific and medical community that solving any of these major diseases -- Parkinson's, Lou Gehrig's disease, Alzheimer's -- could have an enormous impact on the others. There are many reasons for this.

First of all, there's more and more evidence that all of these diseases involve abnormal folding of proteins. If you think of a protein like a towel, you have to fold the towel. If they fold abnormally, it's maybe harder to use that towel. That's what we think happens with these proteins. And ultimately, that's destructive. So some of the proteins may be different for different diseases, but some of the processes that lead to that may be very similar.

[The] second thing is, I think if we cracked one of them, the momentum, the drive to solve others, it would just cascade. And we hope some funding would come with that, too.

And can you speak to Parkinson's' particular potential role in that process as a kind of gateway or flag bearer, whether or not it might lead the way?

Well, for many years, the thought was Parkinson's was the perfect disease to lead the way in terms of solving these diseases. The main reason for that is we were totally focused on one small area of the brain known as substantia nigra -- literally, "black stuff" -- [a] small, pigmented dark area in the brain that sits atop the brain stem. Now, that looked like a pretty easy target, not a big nucleus. We fix that, we get more of the normal chemistry restored in the brain, and we fix the disease.

To some degree, I think that's still true. But we're now learning that Parkinson's is actually much more complex. ...

So would you still call Parkinson's a flag bearer?

... I think that would be true. The one area where that stands out is with what we call cell replacement therapy, the idea of replacing nerve cells that have died. And that's what neurodegenerative disease is: These cells are gone, and we never seem to remake them. So to really cure the disease, you [have] got to replace them, and so most of the work has been done with cell replacement. Transplanting healthy cells into the brain to replace dead, missing ones has been done in Parkinson's, because there is one area, a small area, this substantia nigra, that has a major impact on symptoms.

So I think you're going to see most surgical therapies carried out first in Parkinson's disease. And that's already happening with gene therapy, where genes are inserted in the brain to try to make cells healthier. ... If we get to the point of stem cells going in, all of that will probably be done with Parkinson's first.

... Can you just tell the story of how you came to Parkinson's and how you first sought to figure out this disease?

... Well, the way I got into Parkinson's disease is rather unusual, to say the least, and constitutes probably one of the more remarkable medical detective stories in the annals of medicine. And it really started with my getting called to see a patient who had developed Parkinson's literally over two or three days, yet he was young; that's not typical. It came on quickly; that's not typical. So he was a true medical mystery.

Through a long series of events, including police raids, getting samples of heroin -- because this man was a drug addict -- discovering additional cases that were unrelated except they were heroin abusers, analyzing batches of heroin that we got from police raids, we were eventually able to figure out that there was a tainted heroin on the streets in Northern California and that this heroin was probably the most selective brain toxin ever discovered.

After these addicts shot up, it went like a Nike missile ... and literally killed the same cells in the brain that died in Parkinson's, and we had literally instant Parkinson's disease. Once we figured this out, the implications were enormous. While it was a true tragedy for these young addicts, it gave birth to a renaissance of research in Parkinson's disease. It caused huge interest in the possibility that a simple chemical in the environment might cause the disease. It gave us a tool to study why the cells died, because this compound kills those cells. You can study them at a laboratory, and it led to new therapeutic developments. So it really revolutionized the research in the whole field.

... Can you describe a little bit more about what you saw when you examined those patients?

Well, the first patient that I was called to see was literally frozen like a statue. It was very interesting, because the patient had been seen by both the psychiatry residents and the neurology residents, and there was a huge debate. In fact, that's why I was called. The neurology residents thought it was a psychiatric condition, catatonic schizophrenia, and the psychiatric residents thought it was a neurologic condition, although they didn't quite know what it was.

When I saw the patient, ... [he] had a very unique feature. When you would move his arm, rather than just a gentle pressure, you would get a ratcheting quality. That's called cogwheel rigidity, and this patient had that. And so I knew instantly, we have a neurologic condition on our hands. But what? We had no idea.

It looked like Parkinson's, but Parkinson's doesn't come on abruptly, and it doesn't typically affect young people. After a day or two, we learned two things about this patient. One is that he was totally mentally normal inside, which was a shocker. A medical student actually put a pencil in his hand and asked him to write, held a legal tablet up to his hand. Because he couldn't talk, we didn't know whether he was normal in there or not. And he wrote: "I'm not sure what is happening to me. I only know I can't move; it just won't come out right." And that was the first time that we knew he was mentally normal -- and [also] an exquisite definition, I think, of the feeling a Parkinson's patient must have.

The second thing was, in taking [his] history, we asked him if he was on any medications. And to our shock, he wrote the word "heroin" -- not a traditional medication, but that was our first clue that he was using heroin. And that ultimately led to other heroin addicts and the discovery that the heroin was actually the cause.

... Of course, we didn't know what this was, ... but it looked like Parkinson's, and these patients were totally immobile and unable to move, so we treated it as if it was Parkinson's. And the results were truly dramatic. It literally brought these patients back to life.

I don't know if any of you have seen the movie Awakenings, but it was a very similar experience, where the medication is given, and then half an hour later, the patient starts walking around. ... It responded like Parkinson's disease. So that was a big clue as to what was going on in the brains of these patients.

Can you describe the moment when you made the connection between what was going on chemically with the tainted heroin, with the [toxin] MPTP, and how that related to certain environmental toxins?

Once we discovered what the chemical was -- which was quite a moment in and of itself, because it was very clear that this was going to have major research implications -- something very obvious became apparent, and that is MPTP is metabolized to a compound called MPP+. That is, the body changes it into MPP+; MPP+ is the actual toxin. MPP+ is very similar to a widely used herbicide known as Paraquat. In fact, farmers use Paraquat to burn whole fields. So that was an "aha" moment, because if a compound could cause all of the motor symptoms of Parkinson's, was also very, very chemically similar to an herbicide that's widely used, it really raised the question how many of those things are out there, and could herbicides, pesticides be one of the risk factors in Parkinson's?

A very interesting side to this is that MPP+, the actual toxin that MPTP is made into, was actually developed in the 1970s by a major corporation here in the United States and was going to be sold as an herbicide. It never made it to market. But one can only wonder what it would have been like to have fields full of MPP+, that toxic metabolite of MPTP.

... When we first discovered MPTP and realized that it replicated many features of Parkinson's disease, we had a real hope that this would solve the disease. We thought that MPTP or something like it might cause the disease. I actually made a decision at that point to change my career and see how far we could go. And I thought [in] three to four years we would have an answer. In fact, in three to four years, we did have an answer, and that was that probably MPTP itself was not the cause of Parkinson's. ...

Walk us through, then, a little bit more of that environmental connection: how our understanding of that has evolved, what the leading thinking is right now about the risk, in particular, posed by herbicides and pesticides.

Well, the similarity of MPP+ to Paraquat set off, again, a renaissance of research on environmental factors in Parkinson's disease. There have now been many, many studies that have shown increased risk to a variety of things: farming, use of pesticides, herbicides, both in the environment and in the household, well water. ... Rural living, that's another one. All of these could be surrogates for pesticide, herbicide exposure.

Other things in the environment, certain metals, have been implicated. But again, most of them seem to center around pesticides and herbicides, and more and more studies are pointing that way. Very few individual, specific compounds have been identified. Most of these are modest risk factors, two- to threefold increase in risk. We still don't have a smoking gun, that's for sure. But that's what we're looking for.

I know that research, for example, is going on right now in the Central Valley [of California]. Are we able to say at this point that if you live in certain areas where there's a widespread pesticide exposure that your chances of having Parkinson's go up? Are we at that point?

I don't think we're yet at the point of being able to say unequivocally that if you live in an area where there's more pesticides than other areas, you're at a higher risk. The research would suggest that's the case, but I don't think we're there yet. There are several major studies that could change that.

One is a study that we're doing, looking at all the pesticide applicators in two states, each of whom have to fill out a health questionnaire every two years when they renew their license. So we have a huge amount of data; I think it's 52,000 pesticide applicators over about a 15-year period, some of whom have developed Parkinson's. This, I think, may really answer the question [of] not only are pesticides an increased risk, but also specifically which pesticides. Because it's their profession, they know what they use, as opposed to I couldn't tell you what I sprayed with in the garage last week.

There's also a second major study going on in the Valley here in California, where there's an enormous amount of pesticide use. It's a unique study, because California has kept very careful records since the '70s on pesticide use, so they can tell you how many pounds of pesticide X were sprayed over block Y in year Z. And you can now take little computer overlays of all of these maps on top of the number of cases with Parkinson's.

So we're starting to get some major studies now that I think, in the next year or two, are going to give us some important and maybe definitive data on this. The most exciting development, I think, is the advent of a registry here in the state of California so that every case of Parkinson's is reportable for research purposes. This will tell us for the first time, is the disease increasing, changing with time? Are there pockets or clusters of the disease? Are there differences in rural versus urban areas, socioeconomic differences, etc.? It's hard to believe that we don't have that data now, but we don't have it. It's not available anywhere in the world, and the California Parkinson's Registry will answer all of these questions. So I think we're moving in on it.

How have your own ideas about the disease changed? How do you look at Parkinson's disease differently today than you did when you first got that phone call taking you to the ER?

Well, this is a tough one to cover because it's complicated, but my views of what Parkinson's disease is have changed dramatically in the last few years. When I started my residency, this was a very simple disease: A number of cells die in a small area of the brain that made a chemical called dopamine. When they died, you had no more dopamine. Without dopamine, it's difficult to move. It's a neurotransmitter, a way that nerve cells talk to each other. And that chemical is important to kind of turn on the motor systems so that we can function.

And that was easy. And that's the way we diagnosed it. When dopamine is down, you got rigid, you developed a tremor, gait became slowed and shuffling, etc. Any neurologist can diagnose that.

The revelation started when we got new scanning techniques to much better see where the pathology in the brain is. Then we realized these other areas of brain that are affected have clinical symptoms, too. It's not just the rigidity and tremor. ...

At this point in time, we now know that Parkinson's is a much more complicated disorder. Many different areas of the brain can be affected. It probably evolves in a very specific order, starting in the low brain stem and then eventually affecting other areas, including the nigra, which causes Parkinsonism. But all of these other areas of the brain that are affected can also cause symptoms.

The reason I think it's taken us 150 years to see this is because [patients] don't come to neurologists if they have, say, sleep disorders or loss of sense of smell or even constipation, which is a very bothersome symptom in Parkinson's. They go to a GI specialist or an EENT [eye, ear, nose and throat] specialist. So putting this together has been very difficult. But now I think the picture is really starting to emerge. It's important for a lot of reasons. It may tell us where the disease begins. For instance, if it begins in the gut, that would really focus us on foods. Maybe whatever the agent is that causes this comes in through our food source.

If we're going to slow or halt the disease, we can't have something that just works on one small area of the brain. It has to affect all of these other areas. If we're going to slow the disease down, we probably need to get in there much earlier, when some of these non-Parkinson's symptoms -- let's say sense of smell, as an example -- become affected. That's when we need to step in.

So I think it's really changing the way we think about this disease hugely. And anybody who ignores this, I think, is going to keep going in the wrong direction for a long time.

So how does that complicate your task? Do you now feel, for example, that a cure, the ever-elusive cure, is that much harder to find?

Well, another change in my thinking comes to the word "cure." I think a cure in Parkinson's disease is a long way off. Our original idea was we go in and put new cells into the substantia nigra, that small area of the brain that is affected in the disease, and we're done, and it's a cure. Now that we realize this disease affects so many other areas of the brain, I think the word "cure" is a hard one to use when you talk about Parkinson's.

I do think we have a very real opportunity at slowing or halting the disease. And if we're successful there, for people with mild, early disease, that's very close to a cure. This disease is not like a stroke; by the time the patient gets to the hospital, they're paralyzed. The barn door is open; the horse is gone. It's a very slowly progress[ing] disease, so slow that most patients aren't diagnosed until about the second year of the illness. It's that slow. If we could get in at that point and halt the disease, we could give most patients a near-normal life.

It's kind of like a cure, but not a true cure. But that, I think, is realistic. I think we could see that in my lifetime, my career. But a true cure where we completely remove this disease in the classic sense of the word, I do not think that's going to happen.

The other major implication for this much broader view of Parkinson's is that these surgical treatments where we're putting cells into the nigra or stem cells or fetal cells, or doing gene therapy where we put genes into the nigra, it's only going to fix what we now know to be a small part of this disease. ...

The classic triad of Parkinson's disease is a combination of tremor, stiffness/rigidity and slowness of movement. We call that Parkinsonism. Other things can cause it, but [that's] classic Parkinson's disease. It's what James Parkinson described in 1817. Because we can diagnose that, and we're so focused on it, that triad has stayed with us up until current time. ...

One of the great things, I think, that is dawning on the neurologic community is that all of the other symptoms related to other areas of the brain and peripheral nervous system in Parkinson's are each causing symptoms of a different nature. Not only that, many of these symptoms are as disabling or more disabling than the Parkinson's. In fact, in a recent study from Sydney, Australia, Parkinsonism -- this classic triad of rigidity and slowness and tremor -- didn't even make the top five causes of disability list, because we can treat that.

We have L-dopa; we have deep brain stimulation -- these pacemakers we can put in the brain and reverse the Parkinson's to some degree. We're pretty good at treating the Parkinsonism. What's hitting us, I think big time, is that it's these other features that are now really becoming the disabling ones, partly because we can't treat them and partly because some of them are clearly very disabling: cognitive function, gait and balance. That's a terrifically difficult thing when you can't walk anymore, start falling, etc. So there's a major, I think, revolution really going on of how we think of the disease, how we're going to approach it and where we should be investing our research dollars to prevent disability.

... Does that mean, for example, that looking at stem cell transplants, for example, as the Holy Grail that will fix Parkinson's is at best an incomplete solution?

When we started with neurotransplants -- and we started with fetal cells first, and eventually the hope was stem cells would replace those -- we thought this was going to be easy. We just put the cells in, fix this one small area of the brain, and we cure the disease. And we were very disappointed when that didn't happen. I think now, with our evolving concept of Parkinson's disease, treating this one small area of the brain that we can already treat pretty well with surgical therapies, stem cells, whatever -- it's important, but I think it is no longer the Holy Grail. ...

It's not popular to say that stem cells aren't the answer, but I now believe they are not. I don't think we should give up with them. I think they're going to help other diseases, and eventually they may really help Parkinson's. But I don't think that should be our major focus. The brain is not a pincushion. We can't keep plucking cells in all over the place. ... So I think it's a wake-up call.

Describe a little bit more how complicated this task [of cell transplants into the brain] is. ...

Well, trying to treat Parkinson's disease with cellular transplants -- where we actually put nerve cells into the brain to replace the missing nerve cells, the ones that have died in Parkinson's -- is not easy, not trivial. I think maybe we thought it was going to be, but the comparison I always use is, imagine trying to wire your house after it was built. I mean, when you build a house, all the wiring goes in very early. When the house is built, if you had to do all the wiring afterward, that would be pretty tricky.

Now imagine you're trying to do that in a living brain with 4 billion neurons. This is not going to be easy. I think what we've learned also is that transplanting fetal cells or even stem cells, which are very immature, we're putting those not in a fetal brain or an immature brain; we're putting them in an adult brain. And we're learning there are all types of signals in the adult brain that tell these little guys to go away -- you know, "You don't belong here. You should be in a developing brain."

It seems to me now where we are is every time we turn around and solve one problem we find three more. Can the brain really rewire, putting fetal cells or embryonic cells into an adult brain? Where should those cells go? Will they get back to their target? Will there be feedback circuits? With stem cells, will they even stay dopamine cells, the kind of cells we think the brain needs for Parkinson's? We've learned that those cells often revert back to stem cells after you put them in the brain.

There are so many technical issues here, and I am rather fond of saying only God has successfully wired a human brain so far. This is not going to be easy, and I think the more we learn, the harder it gets, the more daunting the task. That's another reason I'm getting less confident that stem cells are going to solve at least Parkinson's anytime in the near future. ... I think we are a long way away from achieving that and making it work. We don't even understand the reasons, [in] the attempts we've already done, why those have failed. We're still going back to that and trying to figure out, why didn't fetal cells work better than they did?

[In the case of fetal stem cell transplants], it seems like there were problems with it, but there are also these success stories. Why would that be so?

When we first started with fetal cell transplants, the successes were dramatic, so dramatic. And these are small open trials -- six patients, eight patients. Everybody knew they got the transplant. They were so dramatic that it never occurred to us that when we went to a double-blind, meaning neither the patient nor the physician knew if they were getting the cells or not, that wouldn't work. So it can be very dramatic, especially when everybody knows what's going on.

That's why we now do blinded trials where neither the doctor nor the patient knows what they're getting. When two large trials were done blinded, there was little if any therapeutic benefit. That's why we do those trials. So why do you occasionally see a patient that does extremely well? Could that be placebo? We know placebo effect, sugar pill effect -- in this case, sham surgery -- can last years. It could be that. It could be that in a few select patients it really does work. They got it right for reasons we still don't know. ...

Not only that, some groups, some patients had side effects, these abnormal movements as if there was too much dopamine in the brain. They were really quite disabling, and we don't understand why that happens. So we have lack of efficacy, hazardous side effects. This is a tough one to solve. ...

I think where the field is is because you have these two large failed trials, that to do another controlled trial it takes a lot of money, energy and belief that you've got it right this time. Add to that the side effects that some of these patients got, [and] nobody is quite willing to go back and do the large scientific trial. ...

I'm going to ask you about politics and the embryonic stem cell debate, setting aside for a moment whether or not it's the Holy Grail. What's your view of the intertwining of politics and science in this country and how that has impacted the field?

It's a sad day when one of your major challenges in solving a human disease is not scientific but it's political. For some reason, Parkinson's disease research has been plagued with this. We lived through I think it was almost six years of a moratorium that Ronald Reagan put on fetal cell transplantation techniques. We came within two votes in the House of Representatives of overturning that veto, but we had to live with that [for] many years.

Bill Clinton lifted that the second day in office, so we thought it was over and politics was out of science. Wrong. As everyone knows, George [W.] Bush, one of his first major issues -- and I think it was his first major press conference -- was actually on science, and it was on stem cells. So it seemed like we were right back in the same kettle that we were with fetal cells.

I think it's had a disastrous effect on research. It has obviously slowed research in this country. Some of the states, like California, have tried to take matters in their own hands with Prop 71 [to fund stem cell research in that state]. Scientists have left the country. My biggest concern is a whole generation of young scientists that might have gone into this area that haven't. That's invisible right now, but you'll see it in a few years where their careers are no longer in this area. So it's been, I think, a miserable time for everybody, [a] very sad epoch in our history.

How do your resolve the ethical dilemma [created by using fetal cells or embryonic stem cells]? ...

Well, coming to terms with the ethics of both fetal and stem cells, I think, is an issue. I don't think there's anybody here who just says, "Oh, it's not an issue." The issue of when life starts is obviously pretty much irresolvable. Does it start with a twinkle in somebody's eye, or does it start with a certain number of cells in an oocyte [an egg prior to maturation]? This is a never-ending debate. ...

My way of resolving some of the ethical debate with stem cells has to do with the way they're obtained. These stem cells are taken from frozen or stored eggs in a fertility clinic. After a woman donates eggs, they are saved, and they always get more eggs than they need. After a certain period of time, those eggs are thrown away. They are destroyed once a woman has been successfully implanted and has a child.

So the way I look at this is, where is the dilemma here? Throw those eggs away, incinerate them, or try to use them to cure a disease? That's a pretty clear choice to me, and when I have gotten down to that point with people who are against this, most of them are stuck. Most of them haven't even thought it through that far. So at least with stem cells, I think that's a simple choice. Now, of course we're all hoping that all the ethical issues will dissolve, along with some of the medical issues, if we can use adult stem cells, and there is real hope recently in that area.

Before I ask you about that, I just want to ask you one follow-up, because it seems from your earlier points, Bill, that you don't think that stem cells are necessarily the Holy Grail. Does that undermine in any way your argument that holding [stem cell research] back was a disaster? I mean, if it's not the Holy Grail, then holding it back, why would that have been a problem?

Well, I think talking about stem cells [with regard to] Parkinson's disease, I still think there may be a role with those eventually. Clearly, I think stem cells are going to benefit some human disease, and of course the Bush policy has stopped stem cell research for virtually all of those, in my opinion. I think in the long run, it may have made less of a difference in Parkinson's disease, because we're looking at so many other aspects of the disease now. But again, I think sooner or later there's going to be a role for them in some ways. So I do think the hold in science has affected Parkinson's disease. ... I hate to see research stopped at any level, and we all feel a sense of urgency in Parkinson's and its treatments, and I do think we lost ground. ...

The recent breakthrough that demonstrated the ability of getting adult skin cells to revert back to stem cells by inserting a certain number of genes is potentially a huge breakthrough. It suddenly overnight solves our political problems. It's also very exciting because it could solve the problems of immunologic rejection, because you can take the patient's same cells and use those to treat disease. In fact, that may be one reason some of the fetal cell work in Parkinson's didn't work, because it was a different tissue, different patient that it came from. ...

I have two concerns, which I think the people doing the work have also voiced. Are these really going to be genuine stem cells that can really be turned into specific cell types that we need to treat disease? Are they going to be a little bit different? Only time will tell. And then of course there's always a concern that these cells may keep replicating. And we call that cancer. That was a problem with a lot of stem cell work already in experimental animals. So the breakthrough and its potential is enormous. The doing is going to be the key: Are these really going to behave like authentic stem cells, and will they behave themselves and not become cancerous? These are questions that have to be answered. ...

And in the meantime, is it your view that embryonic stem cell research should continue, or should we now just take that off the table because we have these other alternatives?

... I believe it would be a major mistake to stop current research with embryonic stem cells. A huge amount of work has been done. They still may be the winner. ... The fact that we have this new kid on the block -- adult cells that can be turned into stem cells with this new breakthrough -- may change the landscape, but there are still a lot of unanswered questions. It may be yet another false start. ... So I think this should not divert us from the ongoing research. It should be pursued vigorously, and it may change everything, but the answer isn't in yet. ...

There's an old saying in science that research is the process of going up alleys to see if they're blind. And more often than not, they are, but that's what we do. And of course, I think we're all a little bit guilty of maybe hyping our breakthroughs or discoveries more quickly than we [should]. It's a tough thing when you're working directly on a human disease, because I think one of the worst things that we can do is create false hope for patients, and I've seen that again and again: "The cure is just five years away"; "This particular approach is going to solve or cure the disease." That's a cruel thing, and I think we have to guard against it -- we scientists -- and [we] haven't always done the best job at that.

We haven't talked yet about genetics. As you know, that's something that I have a particular personal interest in because of my own family situation. What's the promise of our increased genetic understanding of some triggers for Parkinson's?

In regard to Parkinson's disease, there's been a debate that's at least a century old: [Is this disease] primarily environmental, or is it genetic? And of course, the third possibility is it's both, that there's a gene-environment interaction. There's an old saying that genetics loads the gun and environment pulls the trigger, and that may be the case in Parkinson's.

For many years, the major focus was on environment, but in the last 10 years, there have been now five specific genetic forms of Parkinson's discovered. And that has really changed the landscape for several reasons. Obviously, if someone has a family history of Parkinson's, and you find the gene that causes Parkinson's in that family, that's incredibly important to that family. So far, it's turned out that the genetic forms are very rare. The most common one is at most about 1.5 percent of all Parkinson's, so you're still talking about a very small portion of patients that have a pure genetic form.

Does that mean genetics is not important? Not at all. What has happened is those five genetic forms, although they're very rare, have led us to proteins -- the proteins that are made by the genes where the mutations are -- that have turned out to be hugely important in all patients with Parkinson's disease. And it's actually quite common in medicine that rare genetic forms of a disease turn out to be hugely informative for the more common sporadic form of the disease. That happened in Alzheimer's. ...

If you can unravel the genetic forms, and now you have a very precise target -- you know the gene that's affected; you know the protein it makes -- obviously that could have implications for that family carrying the gene. But I think there's no doubt that at least some of these genes, because they're hitting the same area of the brain that is affected in typical Parkinson's, are going to be very important in all patients with Parkinson's.

... The big remaining question is, just how generalizable is the research on genetic forms to all patients with Parkinson's? I think the evidence is very good that it is generalizable, and it's really leading us in some new directions for treatments. ...

Is part of the importance [of understanding the genetic form of the disease], does that tie back into what you were saying earlier, Bill, about the importance of trying to stop Parkinson's early on? Does genetics provide us some clues that would allow kind of an early identification process?

... One of the hopes now that we do have genetic forms is that we can identify patients who are at risk for the disease because they're carrying the gene but don't have the disease yet. If we could get enough of those patients, we could really learn a lot about the disease before Parkinsonism shows up. What are the earliest symptoms? How do they evolve? Because we can identify these people first and then track them. And [an] even greater hope that may be difficult but we would like to try to do is use those patients to find drugs to slow the disease, because again, we have the genetic marker; they're at risk for the disease. If we could get a large enough group of those patients, start them on drug X to stop or halt the disease, we might be able to prevent the disease from showing up clinically at all. So in the long run, if we could get enough patients, these individuals with genetic Parkinsonism could be enormously helpful in research.

And that's important in part going back to what you said earlier, because it is so slow-progressing. If you can hold someone, not cure them, but kind of hold them early on, it's almost as good as a cure.

Yes. I think our philosophy right now is if you could get in there early, it's very close to a cure, at least practically, because these patients, early in the disease, most patients are just pretty much normal. They can do what they want to, and most of them are still working if they're in that age group. Most of them tell me, if you could stop my disease now, to me it would be just about as good as a cure. And that's where I think the hope is, the realistic hope, at least in the rest of my career.

Yeah. That's exactly what I would say. ... If you could wave your magic wand and keep me where I am right now, that's good; it's good enough. ... Where [are] you, then, on the great question of genetic testing? ... I'll just use my family as an example. If my father had it, I have it, does my daughter get tested? I mean, what's the value? ... Is it really worth knowing that that's in your future?

Well, the issue of genetic testing in Parkinson's is fairly new, because until a decade ago, we didn't have genetic forms that we knew about. Genetic testing is a huge issue, because the fundamental question is, why would you want to know that you're going to get a disease when we can't do anything about it? And so for the most part, I'm not in favor of that. In fact, our own research, we're not allowed to give patients results because it's still considered research.

Once we get a way to slow or halt the disease, it changes dramatically, because of course then there's a remedy; there's a treatment to intervene. So when we do research and identify genes, if somebody really wants to know what they have, we actually require them to have genetic counseling to answer the question, do you really want to know? And most of the time, I think the answer is probably not, not until there's something we can do about it.

The other problem with genetic testing in Parkinson's right now is that many of the mutations, the abnormalities in the genes that have been discovered, we're not quite sure what they mean. And some of the genetic forms, if you carry the gene, the mutation and the gene, your risk of getting the disease is only 30 percent during a lifetime anyway. So now you know you've got a gene that might cause Parkinson's. You've got to worry about that, but you only have a one-third chance of even getting it anyway, and there's nothing to do about it. I would question why people would want to know that at this point. So it's a controversial area. It's one we're just starting to learn how to deal with in Parkinson's, because we now do have these rare genetic forms. And again, this only applies so far to about 1.5 percent of the population [of people with the disease].

On the question of halting [the disease] early on, how important is exercise? ...

I think every neurologist believes exercise is terribly important in Parkinson's disease. There's just no question that patients, many patients, feel much better after exercise. Many of us feel that it's crucial over the long term. Patients that exercise regularly seem to do better, seem to cope with the disease better and stay more functional. That's a very strong belief in the field. Has it ever been proven scientifically? No. But we all encourage it. It's everybody's impression.

And there is some, I think, very good research going on now to prove that exercise really, in a scientific manner, benefits patients day to day. An even bigger question is, could [exercise] really slow the disease progression down? ... There's good experimental data suggesting it could, but certainly not proven at this point.

I heard you give a talk once where you said that exercise is as important as taking your meds.

Yeah. My own belief, seeing patients every day, is that exercise is every bit as important as taking medications. I see that in my patients. I always give them the example of the Tin Man in The Wizard of Oz -- you slow down, rust, freeze up and can't move. And Parkinson's strikes me a bit that way: If you don't use it, you begin to lose function, but if you keep moving, you're not going to rust and freeze up; you're going to stay fluid. And I think you see that every day in the clinic. But now there's some good science going on, I think, to really tell us just how important it is.

And what about the larger question of neuroprotection? You read about things that are being studied, everything from caffeine to nicotine to green tea. Where is that going?

Well, neuroprotection, which is the idea of protecting nerve cells from dying or damage, is another great Holy Grail in the field of neurology. The problem is, I think it's a laboratory concept that jumped into the clinical all too quickly. In a laboratory animal, you can actually measure nerve cells after an experiment. We can't do that in humans. We have no way to really show we've slowed down the progress of cell death in living humans. We've been trying to do that clinically for 20 years and haven't been able to do it.

I now feel that we don't have the tools to do it, and we need to rethink how we're doing this clinically because there are so many agents out there to test. ... So for the moment, where I think we need to focus in clinical trials is delaying disability. We clinicians can measure that. So start a patient on your neuroprotective agent. We can't prove [the neuroprotection], but if disability is really delayed or completely stopped, I think that would be very compelling. ...

... Something that people often talk about is that we're an aging society. The fastest growing segment of our population is the old, the very old. Can you talk some about why this matters, not only for the million or so people who have Parkinson's in this country, but why figuring out these diseases of the aging population is so significant for our country?

Well, I think tackling the major age-related diseases is obviously huge, and it is because of our aging population, and the numbers, the way they're going to go up. So start with the simple thing -- delay disability and suffering by finding ways to slow or halt these diseases or prevent them completely. But of course the socioeconomic cost is going to be enormous to our society. Aged people who are disabled are going to present a tremendous burden on our society, and the numbers are going to go up dramatically.

In fact, we recently published studies showing they're going to start going up almost exponentially. Actually, China drives a lot of that just because of how big the population is. So I won't say it's an emergency, but it's a huge, evolving crisis on how to deal with these diseases. The ultimate answer, of course, is going to be prevention. And while it's really important to focus on strategies to better treat patients that have the disease, slow it down, our other major focus, at least here at the institute, is on prevention -- finding the cause of Parkinson's disease. And you can't do that without epidemiology.

Epidemiology is very expensive. It's time-consuming. It's the least sexy of the research areas because it's so labor-intense. But I think ultimately, for society, the road we have to go is primary prevention. We've got to find the cause of the disease. I think that can happen in my career, in my lifetime. I think there are enough leads, enough evidence that the environment plays a major role. And our epidemiology is now getting sophisticated to the point that we may unravel that one in the not too distant future. I think it's possible.

As someone who's devoted his career to research, why still go down to the clinic?

Well, I see patients every day, and I feel it's critical for several reasons. One is, of course, it keeps you aware of why you're doing this. Patients inspire you. You see what this disease can do, and it makes you want to work harder. Secondly, I believe it's hard to do really good research on a disease when you get too far away from it. You see that in people who just do basic research. Sometimes the research is spot-on, but sometimes they'll start to drift off in a direction that has no relationship to why the research is being done. It's a natural sequence of logical events, but it's not going to go where we need to go.

So I feel that seeing patients keeps me very grounded in the disease and what we need to do to try to cure and help patients. I think it's a reality check and an organic gut check, if you will, as to why we're here and what we need to do to help patients. ...

Parkinson's is an amazing disease in that the patients are always accompanied by their spouses, and I haven't seen that with some other diseases. It's not just the patient that is affected by this; it's the caregiver; it's other family members. And it's huge. With time, it gets bigger and bigger. The love, devotion and caring you see is very inspiring.

I always give my patients a little lecture that they have to take care of the caregiver, because if the caregiver goes down, they go down. So it's a partnership, and they have to work together. But the caregiver is the great untold story. I mean, the burden they carry, the time and effort, particularly when you look at the whole duration of the [disease] -- I mean, many patients, it's 15, 20, often 25 years of their lifetime helping to care for somebody else.

I think we need a lot more attention to caregiver issues. We're trying to develop a very specific program at the Parkinson's Institute on caregiver issues. So it's a major part of this disease and its management, and you can't take your eye off that. ...

If Parkinson's isn't a curable disease, is it a solvable disease?

I think Parkinson's is a solvable disease. And I like the word "solve" because it doesn't use the "cure" word, which I think over-promises. ... I think we're making progress. And I think there's a very good chance we might figure out what the major environmental determinants of the disease are. Once you've done that, you can start talking about primary prevention; that is, preventing the disease altogether.

... If it's solvable, what's keeping you from getting to that solution for it?

Well, it's been said that good science is the absence of prejudice and the presence of money, and I think that's where we are in this disease. We are seeing cutbacks in the National Institutes of Health the likes of which have never been seen before. It is putting a huge stress on the research machine in this country for all diseases, not just Parkinson's. If we're looking at the cause [of Parkinson's], that's even worse, because studies of large populations take enormous amounts of money and time, far more than basic laboratory research. So I do think that we are hamstrung by funding. Scientists are always accused of saying, "Oh, if we just had more money, we could solve this." It's a cliche, but I think it's a very real situation we're in now. It's money, resources and personnel like with any other endeavor. But the pieces are there, so I think funds are huge right now, and it's never been a more difficult time.

If the biggest sugar daddy of them all came to you and said, "Bill, I'll give you all the resources you need if you promise me that you'll solve this disease," is that a bet you'd take?

I would never promise I could solve the disease. What I would do is say, I think there's a very real possibility, with the adequate funding, that we could make major progress on both finding the cause of the disease, which could lead to prevention, and also major progress on finding ways to slow and halt disease progression. I think that's a realistic possibility in my lifetime, my career. I wouldn't have said that five or 10 years ago. A cure, I will not say.

But you've got to have the resources, don't you? ... If you have those, it's doable.

You have to have the resources. NIH is a huge resource -- it's a strapped resource right now -- but NIH isn't enough. You have to have money to chase new leads, to do things that NIH can't fund. I'd say the Michael J. Fox Foundation has played a wonderful role there in giving kind of jump-start, quick money, [to] make things happen. We need a lot more of that.

We need better ties with industry, because we in academic research, we're never going to get a drug to the shelves of pharmacies without a pharmaceutical company. Traditionally in American medicine, there's been a pretty big split between academia and basic research labs and the pharmaceutical industry. We need much better connectivity there so that things can move quickly from the bench to the bedside. I think there does need to be kind of a revelation in the way we do "translational research," meaning bench to bedside. [There's] so much more we could be doing, but all of it requires money.

... Is [Parkinson's] a winnable battle? Is that a useful way to think about this disease right now?

Well, two perspectives. I think patients can win a battle with Parkinson's disease in a way, and that is by never giving up, by doing all the things we can do both medically and they can do physically. They can really hold this disease at bay for quite a long time. Will they ultimately win the battle? Probably not, but they can really fight this disease with success.

Can we win the battle against Parkinson's disease globally, meaning solving the disease? We're not going to totally defeat it, no. But I think there are some huge strides being made right now, and they're in many areas. And I think we could see the results of those in the not too distant future. I wouldn't put a specific time limit on it. I think that's foolish. Science has to go at its own pace. But we are making strides, big ones, insights into both cause and mechanisms of disease. With support, I think we can win that battle.

When I'm talking to a patient with Parkinson's disease, I tell them that this is a disease that we can do a huge amount about, that there's a very good chance that they're going to live out a normal lifespan. The keys to managing the disease are careful treatment, not over-treating; avoiding side effects of therapy; and a good lifestyle, exercise, diet and so forth. [With] careful management, many patients can live a very active life for many years, some [for] many, many years.

It's a disease that you can cope with and deal with if managed correctly, so I give them really a very hopeful message. Depending on when you get it, for many patients I think old age is going to get them first. And that's a hopeful message, I think. Could we do better? Yes. Do some patients have a more rapid form of the disease? Yes.

Is it a curable disease? No. Do we have a way to ebb, to slow the disease down, that's proven? No. But those are all in the pipeline, and I think could happen in our lifetime. So I give patients a very positive message. We have good drugs for this. We can manage the Parkinson's well. If we're careful [in] the way we approach it, you've got a pretty good life to look forward to. ...

A patient of mine died a few months ago, and the obituary said that so-and-so lost the battle with Parkinson's disease. And at his services, a letter was read from a representative in state government, and he said: "Did he lose the battle to Parkinson's? Hell, no. He licked Parkinson's. He beat this disease for 24 years. He didn't lose the battle. He beat that disease."

And in a sense, he really did. This guy was going full bore up to the very end. So in a sense, that congressman just took on that phrase and said, "No way." This guy looked it in the face, fought it head-on, and by God, I think he won.